Design, synthesis and biological evaluation of nuclear receptor-degradation inducers

Yukihiro Itoh, Risa Kitaguchi, Minoru Ishikawa, Mikihiko Naito, Yuichi Hashimoto

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)

Abstract

Compounds that regulate the function(s) of nuclear receptors (NRs) are useful for biological studies and as candidate therapeutic agents. Most such compounds are agonists or antagonists. On the other hand, we have developed specific protein degradation inducers, which we designated as SNIPERs (Specific and Nongenetic IAPs-dependent Protein ERasers), for selective degradation of target proteins. SNIPERs are hybrid molecules consisting of an appropriate ligand for the protein of interest, coupled to a ligand for inhibitor of apoptosis proteins (IAPs), which target the bound protein for polyubiquitination and proteasomal degradation. We considered that protein knockdown with SNIPERs would be a promising alternative approach for modulating NR function. In this study, we designed and synthesized degradation inducers targeting retinoic acid receptor (RAR), estrogen receptor (ER), and androgen receptor (AR). These newly synthesized RAR, ER, and AR SNIPERs, 9, 11, and 13, respectively, were confirmed to significantly reduce the levels of the corresponding NRs in live cells.

Original languageEnglish
Pages (from-to)6768-6778
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number22
DOIs
Publication statusPublished - 2011 Nov 15
Externally publishedYes

Keywords

  • AR
  • ER
  • Protein degradation inducer
  • Protein knockdown
  • RAR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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